The BRAF mutation is associated with a worse initial presentation and prognosis of papillary thyroid carcinoma (PTC) [1,2]. Among several clinicopathological features, extrathyroidal extension (ETE) is significantly associated with the BRAF mutation not only in PTC but in papillary thyroid microcarcinoma (PTMC) [3-6]. Considering that ETE is a key risk stratification and treatment planning parameter, predicting ETE preoperatively is important to determine surgical extent, particularly in patients with PTMC [7-9]. No mixed analysis of the BRAF mutation and predicting ETE had not been reported until recently, although several studies have focused on the association between preoperative ultrasonography (US) findings and postoperative ETE in pathological findings [10,11].

Given that ETE can differ according to the presence of the BRAF mutation, a different strategy to predict ETE is necessary. In addition, because microscopic ETE has minimal clinical implications and significance, predicting gross ETE can be of more benefit. Therefore, in this study, we assessed preoperative parameters associated with gross ETE separately in BRAF positive and negative tumors and evaluated the predictability of gross ETE using important preoperative parameters.

Our results demonstrate that the BRAF mutation is significantly correlated with ETE, and that size and US group are significant predictors of ETE in both the BRAF– and BRAF+ groups. The ETE prediction analysis included preoperative parameters and excluded postoperative findings because the preoperative prediction is important to determine the treatment strategy including surgical extension. The predictive cutoff values for size and US group differed between the two groups. The size cutoff was larger for the BRAF– group, and the BRAF+ group had 100% negative predictive value for ETE in tumors with no capsular contact, whereas it was tumors with <50% contact with the capsule in the BRAF– group.

In this study, the characteristics of BRAF+ tumors were similar to those reported previously. A meta-analysis showed that the BRAF mutation is associated with lymph node metastasis, stage, ETE, tumor size, male sex, multifocality, and absence of a capsule [3]. Our data also shows that the BRAF+ group had more male patients, larger tumors, clinical and pathological central node metastasis, bilaterality, and a positive resection margin in PTMC. One interesting finding was that tumors in the BRAF+ group tended to be located near the capsule, resulting in less proportion of US group A in the BRAF+ group. Moreover, the US showed that the BRAF+ group tended to have more malignant features than those in the BRAF– group, although statistical significance was observed only for the “taller than wide” characteristic. This result agrees with a previous finding that all malignant features are significantly more predominant in BRAF-positive tumors [13].

ETE is categorized as gross or microscopic depending on the extent of invasion. Outcomes from gross ETE are worse than those from microscopic ETE [14,15]. Recent studies have reported that microscopic ETE is not associated with increased recurrence or decreased survival in patients with PTC [16]. In addition, the insignificance of microscopic ETE is equally applied to PTMC, where it has no impact on recurrence in tumors <1 cm [17]. Although our study included an analysis of overall and gross ETE, only gross ETE may be clinically significant.

Several studies have evaluated the predictability of US findings for ETE [10,18]. Although these reports show relative good predictability of ETE, completely predicting positive or negative ETE has not been possible. Moreover, clinical application of US categories has also been difficult. Use of computed tomography, magnetic resonance imaging, and elastography have been suggested for better predictability and easy application in a clinical setting [11,19,20], but complete prediction using preoperative findings remains difficult. In this study, we aimed to simplify US findings into four groups according to the correlation between the tumor and the thyroid capsule. Length of contact and the longest tumor diameter can be compared with a rough guess, resulting in faster tumor categorization using the US findings. Additionally, we considered BRAF mutation status to improve the predictive power with this simplified US grouping.

Several differences in ETE were detected between the BRAF+ and BRAF– groups. Tumor location was significantly correlated with gross ETE in the BRAF– group. Among tumors that contacted the capsule, medially or laterally located tumors had a higher incidence of gross ETE in the BRAF– group. No difference was found in the BRAF+ group according to tumor location, which necessitates further study. The reason why tumors medial or lateral abutting to the capsule had a higher incidence of ETE can be explained using a hypothesis from a previous report [11]. The US probe can compress the patient’s neck and may slightly distort the normal parenchyma around the tumor, which makes the thyroid parenchyma thinner, particularly when the thyroid is pressed between a malignant tumor and the strap muscles. In contrast, the medial and lateral sides of the thyroid are relatively less compressed during a US examination, resulting in low false positive prediction of ETE.

ETE predictive power differed between the BRAF+ and BRAF– groups, as shown for the first time. The multivariate analysis revealed that tumor size and US group were significant predictors of ETE in both the BRAF– and BRAF+ groups. The best predictive ability was found for gross ETE in the BRAF– group (area under the curve, 0.845). Considering that only gross ETE has a clinical impact, predicting gross ETE is more important than predicting overall ETE, as mentioned above. The negative predictive value in both groups was as high as 100% based on tumor size and US group. Therefore, we can exclude gross ETE in BRAF negative tumors <0.7 cm with capsular contact <50% of diameter. Similarly, gross ETE in BRAF positive tumors can also be excluded when the tumor is <0.5 cm with no capsular contact. Consequently, ETE should be strictly excluded in the BRAF+ group with smaller sized tumors and an intraparenchymal location.

The BRAF mutation is associated with aggressiveness of PTC [21-23]. Thus, planning the surgical extent of PTC must be carefully considered. Because of the low mortality rate associated with PTC, particularly with PTMC, postoperative quality of life of patients who undergo thyroidectomies is as important as disease control [24]. Thus, several guidelines for treating differentiated thyroid cancer emphasize that surgical extent should decrease in patients in whom total thyroidectomy and lobectomy are expected to yield similar recurrence or survival rates. However, negative prognosticators, such as ETE and lymph node metastasis, should be excluded when performing a lobectomy. Our results suggest that the BRAF mutation is key to determine the ETE exclusion criteria.

Although our study is valuable as the first study to evaluate the difference in predicting ETE according to the BRAF mutation, this study had several limitations. Firstly, this study has several repetitive demonstration of previous studies which show the BRAF mutation correlated with female gender, multifocality, ETE, lymph node metastasis, and TNM stage. Moreover, Kwak et al. [12] evaluated the association of BRAF mutation and its association with ultrasonographic features in Korean patients with PTMC. However, cutoff criteria was not shown which may be critical to preoperative decision on the extent of surgery. The most of the previous articles deals this matter, while no article show this categorization by BRAF mutation and ultrasonographic findings. Therefore, despite the several repetition in our study, our article can be valuable in that we categorize the preoperative feature and showed numerical cutoff value for helping decision making of the surgical extent. Second, a BRAF mutation preoperative analysis using fine needle aspiration cytology can be incorrect [25]. Thus, a false positive or negative BRAF mutation result could lead to an improper application. Third, this study involved microcarcinoma, which several guidelines suggest require no routine evaluation. Fourth, the degree of contact was assessed visually on preoperative US. Therefore, the results were subjective. Last, our study was based on a retrospective review, which has several inherent biases for analysis. A prospective study with a larger cohort may necessary to overcome this limitation.

In conclusion, our results suggest that the exclusion of ETE can be categorized according to the BRAF mutation, tumor size, and US findings. Tumors <0.7 cm with contact <50% of tumor diameter were factors affecting the absolute cutoff value in the BRAF– group for negatively predicting ETE. Tumors <0.5 cm with no contact with the capsule were factors affecting the cutoff value in the BRAF+ group. Accordingly, a different categorization for excluding ETE is needed based on BRAF mutation status, and our data can be used a background data to decide surgical extent and to counsel patients.